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Preprint WatchModerateJuly 30th, 2026

Human blood vessel organoids reveal a critical role for IGFBP7 in Diabetic Microangiopathy

Pooni, A.; Theofilatos, K.; Boas, L.; Pruktanakul, T.; Alhaque, S.; Romeo, S. G.; Secco, I.; Sneider, E.; Oexner, R.; Schmitt, R.; Zoccarato, A.; Park, S.-H.; Lynham, S.; Zeng, L.; Lee, C. N.; Jackson, T. L.; Modarai, B.; Margariti, A.; Giacca, M.; Shah, A. M.; Zampetaki, A.

IGFBP7 is upregulated in diabetic blood vessel organoids and drives microvascular dysfunction through LGALS1 and LGALS3 as downstream effectors, with both galectins associated with diabetic nephropathy and retinopathy in UK Biobank.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Claidex holds one LGALS3 failure, belapectin in MASH cirrhosis with portal hypertension, recorded as an efficacy failure (belapectin-lgals3-mash-cirrhosis-navigate-phase2b3-efficacy-failure). This preprint places LGALS3 downstream of IGFBP7 in diabetic microvascular disease and reports biobank associations with diabetic nephropathy and retinopathy. The relevant read for a galectin-3 program is positional. If LGALS3 sits downstream of an upstream driver such as IGFBP7, then blocking the galectin alone leaves the driver intact and permits signalling through parallel effectors including LGALS1, which the same work names. That architecture is consistent with the outcome recorded in belapectin-lgals3-mash-cirrhosis-navigate-phase2b3-efficacy-failure, although the disease context here is diabetic microangiopathy rather than liver fibrosis, so the transfer is indirect.

Abstract excerpt

Microangiopathy is a key contributor to diabetic vascular complications. There is currently no effective treatment, and patients are at high risk of major adverse cardiovascular events. We have recently demonstrated that human blood vessel organoids (BVOs) capture key aspects of the microvasculature. Here, employing patient derived BVOs we find that diabetic media treated BVOs display features of diabetic clinical microvascular specimens. Proteomic profiling of diabetic BVOs and their secretome, revealed a robust upregulation of IGFBP7, a protein that was subsequently associated with microangiopathy in UK Biobank. Follow-up studies uncovered an instrumental role of IGFBP7 in the microvasculature and LGALS1 and LGALS3 as its downstream effectors. Underlying their importance in a clinical setting, in the UKB biobank, we observed a strong association of LGALS1, LGALS3 with diabetic nephropathy and retinopathy while in AoU cohort we identified genetic variants in the diabetic microangiopathy signature associated with diabetes diagnosis and cardiometabolic outcomes.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.